Imaging of meningiomas using phenylbenzothiazole, stilbene, or biphenylalkyne derivatives

ABSTRACT

Methods for detecting or ruling out a meningioma in a patient using a phenylbenzothiazole derivative or a stilbene derivative or a biphenylalkyne derivative, and a medical imaging technique such as positron emission tomography/computed tomography are disclosed. In one version of the method, the phenylbenzothiazole derivative is a compound of formula (V):

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a 371 application of PCT/US2011/055753 filed Oct.11, 2011 which claims priority from U.S. Patent Application No.61/392,282 filed Oct. 12, 2010.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under AG016574 andAG011378 awarded by the National Institutes of Health and NationalInstitute on Aging. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a method for the imaging of meningiomas usingphenylbenzothiazole derivatives or stilbene derivatives orbiphenylalkyne derivatives, and using a medical imaging technique suchas positron emission tomography imaging.

2. Description of the Related Art

Meningiomas are the second most common tumor inside the skull with anincidence of approximately six per 100,000, and meningiomas account for13-26 percent of all primary intracranial tumors. Approximately 90% ofmeningiomas are benign, with the rest being more aggressive, or evenmalignant. The benign classifications include meningothelial meningioma,fibrous/fibroblastic meningioma, transitional (mixed) meningioma,psarnrnomatous meningioma, angiomatous meningioma, microcysticmeningioma, secretory meningioma, lymphoplasmacyte-rich meningioma andmetaplastic meningioma. The more aggressive classifications ofmeningiomas include, atypical meningioma, clear cell meningioma,chordoid meningioma, rhabdoid meningioma, papillary meningioma andanaplastic (malignant) meningioma.

Most often standard imaging leads to a confident diagnosis of benignmeningioma. However, the variability of types of meningiomas correspondswith the wide range of possible appearances on standard imaging. Inaddition, many other types of tumors can arise in the membranesoverlying the brain where meningiomas most commonly arise; pia,arachnoid and dura matter. These two factors can lead to a lack ofdiagnostic confidence with conventional diagnostic imaging. This lack ofconfidence can have dramatic and negative effects on a patient's medicalcare.

The majority of meningiomas can be confidently diagnosed based onconventional imaging, such as computed tomography (CT) and magneticresonance imaging (MRI). When a mass in the dura is identified in apatient based on CT or MRI, the most likely diagnosis is meningioma. Aminority of meningiomas contain calcifications, and most meningiomashave higher density then the surrounding brain. These findings are bestevaluated by CT, and both increase confidence in the diagnosis ofmeningioma. Diagnostic confidence is also increased when a dural basedmass has a “dural tail sign”, or when it uniformly enhances withintravenous gadolinium. These findings are best evaluated on MRI.Stability or very slow growth of the mass over many months to years alsoincreases confidence in the diagnosis of meningioma. With these criteriathe majority of meningiomas located in the dura can be diagnosed withconfidence, either at their initial identification on CT and MRI, or intime when they prove to be stable in size.

Beyond CT and MRI there are other adjunct methods currently used to helpdiagnose meningiomas. Angiography has historically been used to suggestthe diagnosis of meningioma. Demonstration of arterial supply frommeningeal vessels and delayed vascular blush on angiography arecharacteristic of meningiomas. However, these findings are neithersensitive nor specific, therefore CT and MRI have proven more usefulthan angiography for the diagnosis of meningiomas. Angiography iscurrently reserved for embolization of meningiomas as a primary therapy,or to reduce the risk of intraoperative hemorrhage. Surgery results indiagnosis/treatment of meningiomas, but reported surgical mortality rateis as high as 14.3%. Lumbar puncture with cerebrospinal fluid (CSF)testing is not useful for diagnosing meningiomas. However, CSF testingis potentially helpful for diagnosing metastatic disease. Leptomeningealinvasion can give rise to tumor cell dissemination in the CSF, which canbe detected by lumbar puncture with cytology, however this is oftenfalsely negative. There are no good laboratory tests available for thediagnosis of meningioma. Meningiomas are most often diagnosedincidentally with imaging. Physical exam and clinical history are oftennormal in patients with meningiomas. When there are signs and symptomsrelated to a meningioma, they are most often non-specific, related tothe mass effect of the meningioma.

Thus, there are problems with the current methods for diagnosingmeningiomas. A minority of meningiomas can not be diagnosed withconfidence based current imaging methods. Meningiomas can look likeother tumors. Meningiomas can occur in locations where other tumors arecommon. Meningiomas can occur elsewhere in the body outside of the dura.Although meningiomas are more common, many less common tumors can mimicthe appearance of a meningioma. Therefore, the diagnosis of meningiomacan not always be made with confidence based on CT and MRI alone, andsometimes when the diagnosis of meningioma is felt to be confident, itis incorrect. This is particularly important in cases where thedifferent diagnoses being considered require very different therapy, orthe real diagnosis is not even considered, such as with metastaticmalignancy.

In patients with meningiomas that have an atypical imaging appearance,the differential diagnosis based on CT and MRI is often broader, lessconfident and includes metastatic disease. Meningiomas can have widelyvaried appearances on CT and MRI, such as cystic changes, adjacentreactive bony proliferation, and adjacent reactive brain parenchymaedema. Examples of meningiomas mistaken for other tumors are plentiful.Misdiagnoses include: orbital metastatic carcinoma; carcinoid tumor;intramedullary spinal tumor; calvarial metastasis; schwannoma;idiopathic hypertrophic pachymeningitis, pituitary adenoma and glial ormetastatic tumors.

In some patients, tumors are identified within the dura in locationswhere other known common tumors can occur. For example, in thecerebropontine angle, the differential diagnosis for a tumor commonlyincludes schwannoma and meningioma, and less likely metastasis,melanoma, sarcoidosis, tuberculosis, Erdheim-Chester, lymphoma,paraganglioma, chordoma. In the region of the sella turcica, thedifferential diagnosis for a tumor commonly includes pituitary adenomaand meningioma, and less likely craniopharyngioma, glioma, gerrninoma,hamartoma, aneurysm, trigeminal schwannoma, pituitary carcinoma,chordoma, metastasis and infection. Meningiomas can occasionally occuroutside of the cranial vault and outside of the dura, making theircorrect diagnosis in these locations much more difficult. When tumorsassociated with the dura are found in the spine, the differentialcommonly includes meningioma, schwannoma, neurofibroma and metastasis.Meningiomas can occur outside the dura in the cervical spine. Other lesscommon extradural locations where meningiomas have been found includethe mediastinum, the ventricle of the brain, lungs, mandible and bone.Rarely meningiomas can even metastasize from the dura to distantlocations, such as to the lungs.

Numerous articles have demonstrated that although most dural tumors canbe confidently diagnosed as meningiomas based on CT and MRI, uncommonlymany other tumors can mimic the appearance of a meningioma. Therefore,the differential for dural based masses that look like meningiomas on CTand MRI is very broad. The general categories for etiologies of thesemeningioma-like dural masses include metastatic disease, lymphoma,multiple myeloma/plasmacytoma, primary dural tumors, infections,inflammatory tumors, and other systemic diseases.

The differentiation between meningioma and dural metastasis inparticular can be very difficult based on current imaging methods. Thisdifferentiation is critical, as often dural metastasis require far moreaggressive medical and surgical management than meningiomas. Sincemeningiomas are common, even in patients with a known metastaticmalignancy, the possibility remains that a dural based mass represents acoincidental meningioma. Dural metastases are found at autopsy in 8-9%of patients with advanced systemic cancer. Prostate, breast, lung andstomach cancer are the most common malignancies metastasizing to thedura. However, renal, bladder, thyroid, colon, rectal, pancreatic,gallbladder, hepatobiliary, cervical, endometrial, choriocarcinoma,mesothelioma, neuroblastoma, sarcoma, seminoma, and otheradenocarcinomas have also been reported to metastasize to the dura. Thediagnosis can be further confused since, the patient's primarymalignancy may be unknown and/or the dural metastasis may be the initialpresentation of systemic malignancy. Furthermore, metastasis to the duracan occur long after the patient has been in complete remission.

There have been advances in imaging for the diagnosis of meningioma.Imaging modalities continue to advance and new techniques in MRI andmolecular imaging, may prove helpful with the differentiation betweenmeningioma and other tumors such as metastasis. The most promisingmodalities are Dynamic contrast MRI with cerebral blood volume mappingand octreotide-analogue based positron emission tomography/computedtomography (PET/CT). Diffusion tensor MRI may help to tell benign fromaggressive meningiomas, based on one small preliminary study. However,diffusion tensor MRI has not been shown to differentiate meningiomasform other types of tumors, such as metastasis.

Dynamic contrast MRI with cerebral blood volume mapping has shown somepromise in helping to differentiate meningiomas from metastasis in atleast two small studies. With this technique intravenous contrastenhanced MRI is used to generate cerebral blood volume maps of the brainand surrounding tissues. These maps are used to measure the relativecerebral blood volume of the tumor compared to brain tissue as aninternal control. These small preliminary studies suggest that therelative cerebral blood volume of meningiomas tends to be higher thenthe relative cerebral blood volume of metastatic tumors. This method isunproven, but shows promise for differentiating meningiomas frommetastasis. It is as yet unclear if dynamic contrast MRI techniques willbe helpful for differentiating meningiomas from other types of tumors.In addition, intravenous MRI contrast agents are required to performthese studies, therefore patients with renal failure are not able toundergo these exams. This is because, patients with renal failure are atrisk to develop nephrogenic systemic fibrosis if they receive gadoliniumcontaining intravenous MRI contrast agents. Nephrogenic systemicfibrosis is a serious condition involving fibrosis of skin, joints,eyes, and internal organs, that has been linked to the use of at least 4of the 5 intravenous MRI contrast agents currently approved by the U.S.Food and Drug Administration; Omniscan, Multihance, Magnevist, andOptiMARK.

Fluorodeoxyglucose (FDG)-PET or FDG-PET/CT can be used in the imaging ofdural tumors. The standard uptake value (SUV) of FDG seen within ameningioma has been shown to be somewhat predictive of how aggressive ameningioma is, and how likely the meningioma will be to recur ifsurgically removed. Meningiomas that do take up significant FDG areusually atypical or even malignant. However, since meningiomas and theother tumors that are seen in the same locations can have variable FDGuptake on FDG-PET/CT, there is limited use of FDG-PET/CT for thediagnosis of meningioma. For example, often the differential for a tumorbased on CT and MRI includes meningioma versus other tumors, such as aschwannoma, that both have little or no FDG uptake. Thus FDG-PET/CT isonly of limited help in the diagnosis of meningioma in these situations.For other tumors, the differential based on CT and MRI includesaggressive meningioma versus other tumors, such as metastasis, that bothhave moderate to high FDG uptake. Again, in this situation FDG-PET/CT isof limited value. When the differential includes benign meningiomaversus metastasis, FDG-PET/CT can be helpful. In this case, if the tumorin question has low or no FDG uptake, then the diagnosis of metastasisis less likely and meningioma more likely. However, even in thissituation other tumors that do not take up FDG remain on thedifferential. Perhaps due to the above reasons, there are no studies todate that show FDG-PET/CT can help differentiate meningiomas from duralmetastasis.

FDG is the only PET tracer currently approved by the U.S. Food and DrugAdministration for tumor imaging. However, many experimental PET tracersare available. PET/CT performed with some of these experimental tracersmay prove helpful in the diagnosis of meningiomas, but most arenonspecific. C11-methionine is taken up by some meningiomas.C11-methionine is taken-up in a nonspecific manner, thought to be due inlarge part to cellular protein production. Therefore C11-methionine isincreased in many actively growing tumors. C11-methionine, similar toFDG, would likely not be taken-up by the majority of meningiomas, whichare not fast growing. C11-methionine would not likely be useful fordifferentiating between aggressive meningiomas and dural metastasis,since both would likely have an increased SUV. 2-F-18-fluoro-L-tyrosineis taken up by some meningiomas. 2-F-18-fluoro-L-tyrosine is taken up ina non-specific manner by cells undergoing DNA synthesis, such as cellsthat are multiplying. Therefore, 2-F-18-fluoro-L-tyrosine has similarbenefits and limitations to C11-methionine with regard to imaging ofmeningiomas. 16 alpha[F-18]fluoro-17 beta-oestradiol (F 18-FES) binds toestrogen receptors and is taken up by some, but not all meningiomas inone small preliminary study. Therefore, F18-FES-PET/CT may not prove tobe highly sensitive for meningiomas. In addition, F18-FES binds to othertumors that express estrogen receptors, such as endometrial cancer,potentially making F18-FES nonspecific for meningiomas.

Radioactive tracers that emit single photons are used in planar nuclearimaging and single photon emission computed tomography (SPECT), and canbe used in imaging of meningiomas. Many single photon tracers areapproved for medical imaging use by the U.S. Food and DrugAdministration. However, like most PET tracers, most single photonemitting tracers are nonspecific for meningiomas. For example,Thallium-201 SPECT imaging is somewhat useful for predictinghistological types of meningiomas, but is nonspecific and is not usefulfor diagnosing meningiomas.

Meningiomas have been shown to express somatostatin 2 receptors and cantherefore be imaged by octreotide (brand name Sandostatin, NovartisPharmaceuticals, CAS#83 150-76-9, ATC code HO1CB02) and othersomatostatin analogues. Octreotide is most commonly used for imaging ofneuroendocrine tumors and can be used in SPECT or PET imaging.Octreotide can be linked to (111)Indium, which is a single photonemitter used in planar and SPECT imaging, or can be linked to 68Gallium,which is a positron emitter used in PET or PET/CT imaging.(111)indium-octreotide is a well studied tracer that binds somatostatinreceptors, and is taken up by meningiomas. (111)Indium-Octreotide isapproved for imaging by the U.S. Food and Drug Administration, whereas68Ga-DOTATOC and 68Ga-DOTANOC are currently experimental labeledoctreotide analogues.1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraaceticacid (DOTA) isused to link 68Ga to one of at least 2 octreotide analogues,1-Nal3-octreotide (NOC) or D Phe1-Tyr3-octreotide (TOC), thus they arecalled 68Ga-DOTANOC or 68Ga-DOTATOC. More is currently published on68Ga-DOTATOC. In one study, 68Ga-DOTANOC-PET/CT may result in lessradiation to patients than 68Ga-DOTATOC-PET/CT.

Octreotide appears to have good sensitivity for meningiomas, but is notperfect. Despite close to 100% of meningiomas reported to expresssomatostatin receptors, specifically receptor 2, sensitivity by imagingis lower. Some of the false negative studies may be due to small volumeof some tumors. However, another theory is that an intact blood brainbarrier may prevent octreotide from labeling some meningiomas. SPECTimaging, even when combined with CT, lacks the resolution of PET imagingand is generally considered inferior as a modality.(68)Gallium-DOTATOC-PET/CT shows better resolution.(68)Gallium-DOTATOC-PET/CT also shows a high signal to background ratioin meningiomas, since the normal brain does not take up octreotide.Octreotide tracers shows strongest uptake in neuroendocrine tumors,neuroectodermal tumors, renal cell carcinoma, small cell lung cancer,breast cancer, prostate cancer and malignant lymphoma. In addition tomeningioma, (68)Gallium-DOTATOC is taken up by other tumors that may beon the differential for a dural mass, like some forms of metastaticdisease, lymphoma, pituitary adenomas, and glial tumors. Octreotideimaging studies may have uses related to meningiomas beyond initialdiagnosis. Octreotide imaging may prove helpful in follow-up postsurgery for recurrent/residual meningioma, as MRI can be confusing dueto postoperative changes. (68)Gallium-DOTATOC-PET/CT has been proposedas a good modality for the planning of focused forms of radiationtherapy, such as fractionated stereotactic radiotherapy, and may seetumor extensions into the dense skull base better than other modalities.

Octreotide studies are time consuming to perform. (111)Indium-octreotideplanar and SPECT imaging is routinely done at 24 hours, but 4 hours maybe sufficient, detecting most meningiomas greater that 5 ml in volume.However, even 4 hours is a long wait when compared to the moreconventional MRI and CT imaging, and is disruptive to patient'sschedules. With (68)Gallium-DOTATOC-PET/CT, the scan is routinelyperformed 120 minutes after injection, with peak/plateau activityoccurring somewhere between 60 and 120 minutes.

Thus, patients who have a history of cancer and find a new tumor in themeningeal membranes that envelope the brain are faced with a commondiagnostic dilemma. Meningiomas are the most common benign intracranialtumors, detected on MRI in 0.9% of normal adults over the age of 45.Approximately 4% of individuals diagnosed with meningiomas have ahistory of cancer. In addition, the incidence of meningeal metastases inpatients with late stage cancer is 9-10%. Approximately 1 out of 5patients with meningeal metastases have limited or otherwise controlledcancer at the time of diagnosis. Therefore if the meningeal tumorrepresents a metastasis it could greatly alter the cancer stage,prognosis and plan of care.

CT and MRI are clearly inadequate for confident distinction ofmeningioma from meningeal metastasis in a single imaging evaluation. Thediagnosis of meningioma is suggested when a tumor is detected in themeningeal membranes that envelope the central nervous system. Typicalmeningiomas enhance uniformly and have an enhancing dural tail (duraltail sign) extending along the meninges. However, meningiomas have awide variety of appearances, and only 60% have this typical appearance.The dural tail sign can be seen with many other tumors, includingmetastases. In fact, approximately 44% of dural metastases have a duraltail according to a recent study from Memorial Sloan-Kettering CancerCenter, and can exactly mimic typical meningiomas on imaging. Theinsufficient specificity of MRI is exemplified in a blinded review ofimaging from patients who had surgical resection of meningeal tumors atthe Cleveland Clinic. In this selected population, the diagnosis ofmeningioma on MRI was only 50% specific and metastatic cancer was themost common mimic. Malignancy can be excluded with multiple follow-upMRI or CT scans over 1 to 2 years if they show stability, or very slowgrowth. Surgical biopsy is the only quick and reliable option availableto definitively differentiate meningiomas from other tumors.

Therapy for meningiomas and metastases differs greatly, and thereforeimprovements in diagnosis would result in clinical benefit. Greater than97% of meningiomas are World Health Organization grade I or II, and areconsidered nonmalignant. When a history of cancer is not clouding thediagnosis, most meningiomas can be monitored clinically and withimaging. A small subset of meningiomas cause symptoms due to masseffect, and therefore surgery or radiation may be required. Chemotherapyis not currently useful for treating meningiomas. These treatments arein stark contrast to the more aggressive, multimodality and systemictherapies that benefit patients with meningeal metastases.Unfortunately, because of inadequate diagnostic confidence with currentimaging, many patients with probable meningiomas are compelled to havesurgery primarily to confirm the diagnosis and only secondarily for thepurpose of treating the tumor. Surgical mortality rates are as high as7% and significant and permanent morbidity rates are as high as 40%,depending on location of the tumor.

From the foregoing, it can be appreciated that there is a need foralternative methods for detecting or ruling out a meningioma in apatient.

SUMMARY OF THE INVENTION

The present invention addresses the foregoing needs by providing amethod for the imaging of meningiomas using a phenylbenzothiazolederivative or a stilbene derivative or a biphenylalkyne derivative thataccumulates within meningiomas such that the meningiomas can bediagnosed by a medical imaging technique such as positron emissiontomography imaging.

In one aspect, the invention provides a method for detecting or rulingout a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (I):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. R₁, R₂ and R₃ in Formula (I) can be independentlyselected from H, OH, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted amino,and substituted or unsubstituted carboxylate. At least one of the atomsin R₁ or R₂ or R₃ is replaced with ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br,⁷⁶Br, ¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and^(99m)Tc. The step of acquiring the image can be performed using animaging method selected from positron emission tomography imaging,single photon emission computed tomography imaging, positron emissiontomography with concurrent computed tomography imaging, positronemission tomography with concurrent magnetic resonance imaging, singlephoton emission computed tomography with concurrent computed tomographyimaging, or any combination thereof.

In another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (II):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. R₂ and R₃ in Formula (II) can be independentlyselected from H, OH, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted amino,and substituted or unsubstituted carboxylate. At least one of the atomsin R₂ or R₃ is replaced with ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thestep of acquiring the image can be performed using an imaging methodselected from positron emission tomography imaging, single photonemission computed tomography imaging, positron emission tomography withconcurrent computed tomography imaging, positron emission tomographywith concurrent magnetic resonance imaging, single photon emissioncomputed tomography with concurrent computed tomography imaging, or anycombination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (III):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. R₁ and R₃ in Formula (III) can be independentlyselected from H, OH, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted amino,and substituted or unsubstituted carboxylate. At least one of the atomsin R₁ or R₃ is replaced with ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thestep of acquiring the image can be performed using an imaging methodselected from positron emission tomography imaging, single photonemission computed tomography imaging, positron emission tomography withconcurrent computed tomography imaging, positron emission tomographywith concurrent magnetic resonance imaging, single photon emissioncomputed tomography with concurrent computed tomography imaging, or anycombination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (IV):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. R₁ and R₂ in Formula (IV) can be independentlyselected from H, OH, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted amino,and substituted or unsubstituted carboxylate. The step of acquiring theimage can be performed using an imaging method selected from positronemission tomography imaging, single photon emission computed tomographyimaging, positron emission tomography with concurrent computedtomography imaging, positron emission tomography with concurrentmagnetic resonance imaging, single photon emission computed tomographywith concurrent computed tomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (V):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (VI):

is administered to a patient. R₄ can be selected from H, OH, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted amino, and substituted or unsubstitutedcarboxylate; n can be an integer from 0 to 10, and X can be selectedfrom the group consisting of ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thecompound is targeted to any meningiomas in the patient. An image is thenacquired to detect the presence or absence of any meningiomas inside theskull or elsewhere within the patient. The step of acquiring the imagecan be performed using an imaging method selected from positron emissiontomography imaging, single photon emission computed tomography imaging,positron emission tomography with concurrent computed tomographyimaging, positron emission tomography with concurrent magnetic resonanceimaging, single photon emission computed tomography with concurrentcomputed tomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (VII):

is administered to a patient. R₄ can be selected from H, OH, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted amino, and substituted or unsubstitutedcarboxylate; n can be an integer from 0 to 10, and X can be selectedfrom the group consisting of ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thecompound is targeted to any meningiomas in the patient. An image is thenacquired to detect the presence or absence of any meningiomas inside theskull or elsewhere within the patient. The step of acquiring the imagecan be performed using an imaging method selected from positron emissiontomography imaging, single photon emission computed tomography imaging,positron emission tomography with concurrent computed tomographyimaging, positron emission tomography with concurrent magnetic resonanceimaging, single photon emission computed tomography with concurrentcomputed tomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (VIII):

is administered to a patient. R₄ can be selected from H, OH, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted amino, and substituted or unsubstitutedcarboxylate; n can be an integer from 0 to 10, and X can be selectedfrom the group consisting of ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thecompound is targeted to any meningiomas in the patient. An image is thenacquired to detect the presence or absence of any meningiomas inside theskull or elsewhere within the patient. The step of acquiring the imagecan be performed using an imaging method selected from positron emissiontomography imaging, single photon emission computed tomography imaging,positron emission tomography with concurrent computed tomographyimaging, positron emission tomography with concurrent magnetic resonanceimaging, single photon emission computed tomography with concurrentcomputed tomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (IX):

is administered to a patient. R₄ can be selected from H, OH, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted amino, and substituted or unsubstitutedcarboxylate; n can be an integer from 0 to 10, and X can be selectedfrom the group consisting of ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br,¹⁸F, ¹⁹F, ⁶⁸Ga, ⁸²Rb, ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl, and ^(99m)Tc. Thecompound is targeted to any meningiomas in the patient. An image is thenacquired to detect the presence or absence of any meningiomas inside theskull or elsewhere within the patient. The step of acquiring the imagecan be performed using an imaging method selected from positron emissiontomography imaging, single photon emission computed tomography imaging,positron emission tomography with concurrent computed tomographyimaging, positron emission tomography with concurrent magnetic resonanceimaging, single photon emission computed tomography with concurrentcomputed tomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (X):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (XI):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (XII):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient. In this version of the method, adetectable amount of a compound of formula (XIII):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (XIV):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In still another aspect, the invention provides a method for detectingor ruling out a meningioma in a patient. In this version of the method,a detectable amount of a compound of formula (XV):

is administered to a patient. The compound is targeted to anymeningiomas in the patient. An image is then acquired to detect thepresence or absence of any meningiomas inside the skull or elsewherewithin the patient. The step of acquiring the image can be performedusing an imaging method selected from positron emission tomographyimaging, single photon emission computed tomography imaging, positronemission tomography with concurrent computed tomography imaging,positron emission tomography with concurrent magnetic resonance imaging,single photon emission computed tomography with concurrent computedtomography imaging, or any combination thereof.

In yet another aspect, the invention provides a method for detecting orruling out a meningioma in a patient that has been administered adetectable amount of a radiolabeled phenylbenzothiazole derivative or astilbene derivative or a biphenylalkyne derivative chosen from any ofthe compounds of Formulas (I) to (XV) above. In the method, an image isacquired wherein the image indicates the presence or absence of anymeningiomas in the patient. The imaging can be acquired using a methodselected from positron emission tomography imaging, single photonemission computed tomography imaging, positron emission tomography withconcurrent computed tomography imaging, positron emission tomographywith concurrent magnetic resonance imaging, single photon emissioncomputed tomography with concurrent computed tomography imaging, or anycombination thereof.

In any of the above methods, the presence of any meningiomas in thepatient can be indicated by an image in which meningiomas showedactivity of the compound of any of Formulas (I) to (XV) greater thannormal adjacent tissues imaged. In any of the above methods, thepresence of any meningiomas in the patient can be indicated by a brainimage in which meningiomas showed activity of the compound of any ofFormulas (I) to (XV) greater than any other intracranial tumors imaged.In any of the above methods, the presence of any meningiomas in thepatient can be indicated by a brain image in which meningiomas showedactivity of the compound of any of Formulas (I) to (XV) greater than anymetastases, pituitary macroadenomas, schwannomas, or ependymomas imaged.In any of the above methods, the presence of any meningiomas in thepatient can be indicated by an image in which meningiomas showedactivity of the compound of any of Formulas (I) to (XV) greater than anymetastases imaged.

It is one advantage of the invention to provide a method for diagnosingmeningiomas in those patients where an intracranial tumor is identifiedthat might be a meningioma based on conventional computed tomographyand/or magnetic resonance imaging, but further clarification with a moredefinitive test is desired. Many meningiomas are diagnosed confidentlyby a radiologist using computed tomography and/or magnetic resonanceimaging (although sometimes incorrectly). A few tumors are difficult todiagnose and the radiologist gives a differential diagnosis. Surgicalbiopsy in these cases is usually diagnostic, but is invasive and carriessignificant risk, and is rarely ordered. Re-imaging many months/yearslater with CT/MRI, showing stability can help confirm a meningiomadiagnosis as opposed to cancer, which would be expected to grow morerapidly. Many clinicians and patients may desire a more definitive testthan CT/MRI for meningioma, despite the radiologist's sense ofconfidence in the diagnosis, since cancer is not completely ruled out.The present invention provides such a diagnostic method.

It is another advantage of the invention to provide a method fordiagnosing meningiomas in those patients who have a new diagnosis ofmalignancy and who have an intracranial tumor that could be a meningiomaversus metastasis. It is not uncommon for a patient to have anintracranial metastasis. It is also not uncommon to have both amalignancy and a meningioma (as both cancer and meningiomas are common).In the setting of a patient with a known malignancy, a definitivediagnosis of meningioma by CT/MRI is much harder for the radiologist, asmetastasis are well known to be able to mimic meningiomas. There aremany articles describing metastasis that were misdiagnosed asmeningiomas, and vice versa. Often the correct diagnosis is critical forpatient management, and clinicians are forced to choose among badoptions. In one suboptimal treatment, the physician assumes theintracranial tumor is a metastasis and gives chemotherapy and/orradiation and the patient accepts the side effects, or the physicianorders surgical biopsy/resection of the tumor and the patient acceptsthe potential complications. In another suboptimal treatment, thephysician assumes the intracranial tumor is a meningioma and waits tore-image months later with no therapy, recognizing that a metastasiswould continue to grow, or the physician treats the patients knowncancer and other metastasis with appropriate therapy, recognizing thatif the intracranial tumor is a metastasis, their efforts are futile interms of possible cure. The present invention solves these problems byproviding a diagnostic method that differentiates meningioma versusmetastasis.

These and other features, aspects, and advantages of the presentinvention will become better understood upon consideration of thefollowing detailed description, drawings, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows axial images of a brain of a patient obtained using MRI aswell as PET/CT using the compound of formula (V). The MRI showed a massalong the right tentorium cerebella, a presumed meningioma, and thecombination of PET and CT images showed intense activity with thecompound of formula (V) at the meningioma.

FIG. 2 shows sagittal and axial images of a brain of a patient obtainedusing MRI as well as PET/CT using the compound of formula (V). The MRIshowed a mass along the tuberculum sellae and planum sphenoidale, apresumed meningioma, and the combination of PET and CT images showedintense activity with the compound of formula (V) at the meningioma.

FIG. 3 shows axial, sagittal and coronal images of a brain of a patientobtained using CT and MRI, as well as PET/CT using the compound offormula (V). The images show meningioma arising from the meninges of theright tentorium and compressing the right posterior temporal lobe.

FIG. 4 shows meningiomas compared to metastases on PET using thecompound of formula (V) fused to MRI.

FIG. 5 shows meningiomas compared to other intracranial tumors on PET/CTusing the compound of formula (V) and MRI.

FIG. 6 shows meningioma tissue stains compared to a schwannoma andamyloid plaques in the cerebral cortex.

DETAILED DESCRIPTION OF THE INVENTION

The method of the invention exploits the ability of radiolabeledphenylbenzothiazole derivatives or stilbene derivatives orbiphenylalkyne derivatives to cross the blood brain barrier in vivo andto accumulate in a meningioma. The method of the invention determinesthe presence (if any) and location of a meningioma at a part (e.g.,brain) of the body of a patient. The method includes the step ofadministering of a detectable amount of a pharmaceutical compositionincluding a radiolabeled phenylbenzothiazole derivative or a stilbenederivative or a biphenylalkyne derivative chosen from the compounds ofFormulas (I) to (XV) above to a patient. A “detectable amount” meansthat the amount of the detectable compound that is administered issufficient to enable detection of accumulation of the compound in ameningioma by a medical imaging technique. A “patient” is a mammal,preferably a human, and most preferably a human suspected of ameningioma.

In vivo detection of the accumulated compound in the meningioma can beachieved by medical imaging techniques such as positron emissiontomography (PET), computed tomography imaging (CT), magnetic resonanceimaging (MRI), single-photon emission computed tomography (SPECT) andany combinations thereof. In the radiolabeled phenylbenzothiazolederivative or stilbene derivative or biphenylalkyne derivative chosenfrom the compounds of Formulas (I) to (XV) above, the type of medicalimaging device is a factor in selecting a given label. For instance, theisotopes ³H, ¹¹C, ¹³C, ¹⁴C, ⁷⁵Br, ⁷⁶Br, ¹⁸F, ¹⁹F, ⁶⁸Ga, ¹¹¹In, ¹²³I,¹²⁵I, ¹³¹I, and ^(99m)Tc are particularly suitable labels for in vivoimaging in the methods of the invention. The type of medical imagingdevice used will guide the selection of the isotope. For PET detection,the radiolabel will be a positron-emitting radionuclide which willannihilate to form two gamma rays which will be detected by the PETcamera. For SPECT detection, the chosen radiolabel will produce minimalif any particulate emission, but will produce a large number of photons.

Concurrent use of two or more of the medical imaging techniques such asPET, CT, MRI, and SPECT can be advantageous in the method of theinvention. For example, PET images can demonstrate better correlation topatient anatomy on a CT taken at the time of PET than to patient anatomyon a separate CT (usually taken before the PET image). By using a PETand CT taken back to back with the patient in the same position in themethod of the invention, the risk of errors due to motion can bereduced.

For purposes of in vivo imaging, the type of detection instrumentavailable is a major factor in selecting a given label. For instance,¹⁹F or ¹³C are suitable for MRI; ¹⁸F, ¹¹C, ¹³N, ¹⁵O, ⁷⁵Br, ⁷⁶Br, ⁸²Rbare suitable for PET; and ¹¹¹In, ¹²³I, ¹²⁵I, ¹³¹I, ²⁰¹Tl and ^(99m)Tcare suitable for SPECT imaging. ³H or ¹⁴C are suitable for in vitroimaging studies.

Administration to the patient of a pharmaceutical composition includinga radiolabeled phenylbenzothiazole derivative or stilbene derivative orbiphenylalkyne derivative chosen from the compounds of Formulas (I) to(XV) above for in vivo detection of the accumulated compound in themeningioma can be accomplished intravenously, intraarterially,intrathecally, intramuscularly, intradermally, subcutaneously, orintracavitary. Dosage can vary from 0.001 μg/kg to 10 μg/kg. In themethod of the invention, sufficient time is allowed after administrationsuch that the radiolabeled phenylbenzothiazole derivative or stilbenederivative or biphenylalkyne derivative can accumulate in anymeningioma.

We have discovered that the compound of formula (V) above accumulateswithin meningiomas and recurrent meningiomas. We have also shown thatmeningiomas and recurrent meningiomas can be diagnosed using positronemission tomography using the compound of formula (V) and relatedradiolabeled phenylbenzothiazole derivatives. Based on this discovery,we propose a new use of the compound of formula (V) and relatedradiolabeled phenylbenzothiazole derivatives, and a new medicalindication for positron emission tomography using the compound offormula (V) and related radiolabeled phenylbenzothiazole derivatives,i.e., the imaging of tumors to diagnose meningiomas without the need forbiopsy. Positron emission tomography using the compound of formula (V)and related radiolabeled phenylbenzothiazole derivatives could also beused for planning stereotactic radiation therapy. Positron emissiontomography using the compound of formula (V) and related radiolabeledphenylbenzothiazole derivatives may also be useful for diagnosingrecurrent/residual meningioma post surgical resection.

One non-limiting example method of imaging involves the use of anintravenous injectable molecule such as the compound of formula (V). Inthe compound of formula (V), a positron emitting (i.e. radioactive)¹¹carbon atom gives off a positron, which subsequently annihilates andgives off coincident gamma radiation. This high energy gamma radiationis detectable outside the body through the use of positron emissiontomography imaging, or positron emission tomography concurrent withcomputed tomography imaging (PET/CT). With PET/CT, the location of theinjected and subsequently accumulated molecules of Formula (V) withinthe body can be identified. Our discovery shows that meningiomasaccumulate molecules of Formula (V), and that meningiomas are detectableby PET/CT. Our data suggests that other tumors common to the meninges,such as schwannomas, do not accumulate molecules of Formula (V). Sinceother tumors may not accumulate molecules of Formula (V), PET/CT usingthe compound of formula (V) can help differentiate meningiomas fromother types of tumors.

The compound of formula (V), Pittsburgh complex B (PiB), is abenzothiazole derivative developed as a positron emission tomography(PET) imaging agent. PiB was specifically designed to bind to amyloidplaques in the brains of patients with Alzheimer disease. (See, Mathis CA, Wang Y, Holt D P, Huang G F, Debnath M L, Klunk W E, “Synthesis andevaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloidimaging agents”, J Med Chem 2003; 46:2740-54). PiB is an analogue ofThioflavin-T, a fluorescent tissue stain that is commonly used todiagnose Alzheimer disease on autopsy brain tissue. To our knowledge,this is the first report of patients with intracranial tumors imagedwith PiB PET/CT. Of note, patients with brain tumors are specificallyexcluded from Alzheimer's Dementia Neuroimaging Initiative (ADNI), alarge multicenter trial that includes amyloid PET imaging.

EXAMPLES

The following Examples have been presented in order to furtherillustrate the invention and are not intended to limit the invention inany way.

A compound of formula (V) below was selected for investigation.

The compound of formula (V) is also known as[N-Methyl-¹¹C]₂-(4′-methylaminophenyl)-6-hydroxybenzothiazole (CASNumber 566170-04-5) or Pittsburgh compound B (PiB). It can besynthesized using the methods described in U.S. Pat. No. 7,270,800.

Example 1

An Alzheimer's imaging database of two hundred forty-one patients wasreviewed. Some of the patients had a history of cognitive impairmentthat might be due to early Alzheimer's disease and some were normalcontrols. All patients had been imaged by at least one MRI, as well asby FDG-PET/CT and PET/CT using the compound of formula (V). MRI reportsof all patients were reviewed for possible meningiomas and other tumors.Seven patients were found to have the diagnosis of presumed meningiomabased on MRI and sometimes also on CT. The diagnostic confidence of theradiologists interpreting the studies varied slightly, depending onfactors such as tumor location and previous imaging. Of these seventumors, six showed intense uptake of the compound of formula (V) onPET/CT. One showed some uptake, but was difficult to evaluate presumablybecause of its small size (˜4 mm. thick). Tumors smaller than 7millimeters are generally considered too small to be evaluated by PET orPET/CT. This is an excepted limitation of PET or PET/CT as a modality.Our data confirm that meningiomas have a variable uptake onfluorodeoxyglucose (FDG)-PET/CT with four showing no uptake and twoshowing mild uptake, and one too small to evaluate. None of themeningiomas in the series would be classified as atypical or aggressivebased on MRI or CT imaging. One presumed extracranial schwannoma wasseen, showing mild uptake on FDG-PET/CT, but no uptake on PET/CT usingthe compound of formula (V). Other tumors were also seen with little tono uptake of the compound of formula (V).

FIG. 1 shows axial images of a brain of a patient (identified as Patient#1 in FIG. 1) obtained using MRI as well as PET/CT using the compound offormula (V) (identified as PiB in FIG. 1). The MRI showed a mass alongthe right tentorium cerebelli, a presumed meningioma, and thecombination of PET and CT images showed intense activity with PiB at themeningioma.

FIG. 2 shows sagittal and axial images of a brain of a patient(identified as Patient #4 in FIG. 2) obtained using MRI as well asPET/CT using the compound of formula (V) (identified as PiB in FIG. 2).The MRI showed a mass along the tuberculum sellae and planumsphenoidale, a presumed meningioma, and the combination of PET and CTimages showed intense activity with PiB at the meningioma.

Example 2

In Example 1, we identified six patients with meningiomas >5 millimetersin size that showed positive uptake of the compound of formula (V) onPET/CT. We identified three more patients with four presumedmeningiomas. All three patients were imaged by PET-CT using the compoundof formula (V), FDG PET-CT and MRI within as part of the ongoing amyloidimaging study. In one patient, there are two meningiomas. One is in theorbit, and is therefore extracranial. This orbital meningioma waspreviously resected and pathologically shown to be a meningioma in 1969,and pathology was confirmed later at our institution. It has now regrownwithin the orbit. The other meningioma is along the falx. Both show aviduptake of the compound of formula (V). There were two other patientswith a single meningioma with uptake of the compound of formula (V).Therefore, there are a total of ten presumed meningiomas that showuptake of the compound of formula (V) on PET/CT.

Example 3

In Examples 1 and 2, we identified ten patients with meningiomas >5millimeters in size that showed positive uptake of the compound offormula (V) on PET/CT. We identified three more examples of presumedmeningiomas that show activity using the compound of formula (V) onPET-CT, for a total of thirteen. All of these formula (V) avidmeningiomas are >5 millimeters in size. We also identified three morepresumed meningiomas that showed some positive uptake of formula (V),but were non-diagnostic due to common limitations of PET/CT imaging. Oneof these non-diagnostic presumed meningiomas was too small to evaluateby PET or PET/CT. One of these non-diagnostic presumed meningiomas wasnecrotic/cystic centrally with a 4 millimeter rim of tumor, and istherefore effectively also too small to evaluate by PET or PET/CT. Theother of these non-diagnostic presumed meningiomas was only seen in thelast 2 slices of PET data, an area considered to be uninterpretable. Inaddition, this patient moved during the exam, causing artifact.Therefore, our data show all thirteen out of thirteen presumedmeningiomas that were >5 millimeters in size and within the diagnosticfield of view of PET-CT showed positive uptake with formula (V) and werepositive on PET/CT imaging. One of these patients with a presumedmeningioma was imaged two times with formula (V), with many months inbetween, and showed the same positive results. Therefore, we have shownthat imaging of meningiomas with formula (V) and PET/CT is reproducible.In addition to presumed meningiomas we found within this group ofpatients 25 different types of tumors and non-neoplastic lesions,including a presumed shwannoma, hamartoma, ependymoma and pituitaryadenoma, which all showed only background uptake or no uptake withformula (V) and were not positive on PET/CT. Therefore, we have shownthat imaging of meningiomas with formula (V) and PET/CT is specific.

Example 4 Summary of Example 4

Intracranial metastases and other tumors often mimic the appearance ofcommon benign meningiomas on CT and MRI, leading to delayed therapy,misdiagnoses and surgical biopsies. Pittsburgh compound B (PiB) is apositron emission tomography (PET) imaging radiotracer. PiB was designedto bind beta-amyloid in the brain and similar compounds are in FDAtrials for use as imaging biomarkers of Alzheimer's disease.Unexpectedly, we observed that meningiomas accumulate PIB. We evaluatedif meningiomas could be diagnosed with PiB PET/CT imaging, andfurthermore, whether such imaging might be due to amyloid withinmeningiomas. 834 adult patients who underwent MRI, F18-FDG PET/CT andC11-PiB PET/CT imaging as part of the Mayo Clinic Study of Aging wereretrospectively reviewed. Presumed meningiomas and other intracranialtumors detected on MRI were identified and all available imaging wasreviewed. Tumor tissue sections were stained with PiB, highlyfluorescent 6-CN-PIB, and anti-amyloid antibodies. All 16 meningiomasidentified by strict imaging criteria showed PiB activity greater thannormal adjacent tissues. All other intracranial tumors imaged, includingmetastases, pituitary macroadenomas, schwannomas and an ependymoma,showed PiB activity equal or less than normal adjacent tissue. Tissuesections from meningiomas stained brightly positive with PiB, showing adistinct staining pattern, but stained negative with amyloid specificantibodies. It was concluded that meningiomas take up PiB, and cantherefore be identified with PET. This finding could lead to asubstantial advance in the medical care of people with meningioma-likebrain tumors. Tissue stains suggest that PiB is binding to somethingother than amyloid within meningiomas.

Methods

Patient Selection

The radiologic interpretations of MRI, CT and FDG PET/CT scans from apopulation of 834 people who participated in the population-based MayoClinic Study of Aging (MCSA) from March 2006 through September 2011 werereviewed for the presence of tumors or other brain lesions. (See,Kantarci K, Lowe V, Przybelski S A, et al., “Magnetic resonancespectroscopy, {beta}-amyloid load, and cognition in a population-basedsample of cognitively normal older adults”, Neurology 2011; 77:951-8;and Roberts R O, Geda Y E, Knopman D S, et al., “The Mayo Clinic Studyof Aging: design and sampling, participation, baseline measures andsample characteristics”, Neuroepidemiology 2008; 30:58-69.) Participantswere randomly selected for recruitment in the MCSA from a population ofolder adult residents of Olmsted County, Minnesota, USA. Those withneurological, psychological or systemic illnesses were not excluded.Individuals with dementia, or those unable to be imaged for medicalreasons were excluded. All patients were imaged with C11-PiB PET/CT,F18-FDG PET/CT and non-contrast MRI at least once as part of the study.Any additional patient imaging and clinical history was then reviewed.

Tumors found in any of the subjects were then categorized as possiblemeningiomas or non-meningiomas based on the reading of the reportingneuroradiologist. Possible meningiomas were further reviewed as a group.A more strict set of criteria were applied to select a subset of thepossible meningiomas that were designated “high-likelihood meningiomas”for further analysis and were defined by (1) tumors that were confirmedto be enhancing on diagnostic MRI (obtained separately for clinicalpurposes) and (2) tumors that had greater than two years of follow-upimaging confirming no growth or slow growth (1-2 mm per year). When thelead diagnosis of the identified tumor was metastasis, the diagnosis wasconfirmed by biopsy or autopsy. All tumors smaller than 5 mm thick wereexcluded, given they fall below the generally accepted lower limits ofPET/CT resolution.

Imaging

PET imaging was performed as part of the Mayo Clinic Study of Aging aspreviously described. (See Kantarci K, Lowe V, Przybelski S A, et al.,“Magnetic resonance spectroscopy, {beta}-amyloid load, and cognition ina population-based sample of cognitively normal older adults”, Neurology2011; 77:951-8.) PiB PET/CT, then FDG PET/CT were performed on the sameday. PET/CT imaging was performed on a 690XT or DRX PET/CT tomograph (GEHealthcare). The PET sinograms were reconstructed using a fully-3D OSEMalgorithm into a 30 cm field of view; the pixel size was 1.2 mm and theslice thickness was 3.27 mm (DRX) or 1.96 mm (690XT). CT imaging wasobtained immediately prior to PET acquisition and used for attenuationcorrection. Cerebral PiB retention, a marker of amyloid deposition, wasmeasured as previously described. (See Kantarci K, Lowe V, Przybelski SA, et al. “Magnetic resonance spectroscopy, {beta}-amyloid load, andcognition in a population-based sample of cognitively normal olderadults”, Neurology 2011; 77:951-8.)

Noncontrast MRI studies were performed as part of the Mayo Clinic Studyof Aging using a standard research protocol as previously described.(See Kantarci K, Lowe V, Przybelski S A, et al., “Magnetic resonancespectroscopy, {beta}-amyloid load, and cognition in a population-basedsample of cognitively normal older adults”, Neurology 2011; 77:951-8.)Additional imaging obtained for clinical purposes was also reviewed,including contrast enhanced MRI exams when available. MRI images werefused with PET/CT data when necessary to confirm anatomic registrationof PET activity with brain tumors. Fusion was performed with apoint-based rigid registration method using OsiriX Open-Source PACSWorkstation, 64-bit version 3.9.4 (Pixmeo).

Materials

C11-PiB and F18-FDG were produced on-site in a Mayo Clinic cyclotronfacility. Production and quality control methods are described at Lowe VJ, Kemp B J, Jack C R, Jr., et al., “Comparison of 18F-FDG and PiB PETin cognitive impairment”, Journal Of Nuclear Medicine: officialpublication, Society of Nuclear Medicine 2009; 50:878-86. 6-CN-PiB wassynthesized as previously described at Ikonomovic M D, Klunk W E,Abrahamson E E, et al., “Post-mortem correlates of in vivo PiB-PETamyloid imaging in a typical case of Alzheimer's disease”, Brain: AJournal Of Neurology 2008; 131:1630-45. Non-radioactive PiB, used fortissue staining, was purchased from ABX. NCL-B-Amyloid anti-amyloidantibody was purchased from Leica.

Tumor Selection for Tissue Staining

The Department of Pathology, Mayo Clinic Rochester Tumor TissueRegistry, contains tumor samples procured by autopsy and surgery.Meningiomas, brain metastases and other tumors were identified bysearching CoPath, a Mayo Clinic electronic pathology database of tumorscollected since 1982. Tumor type was confirmed by viewing H&E stainedslides under a light microscope.

Tissue Stains

Fresh cut 5 μm thick sections were used. Each staining run includednormal brain and Alzheimer diseased brain as controls. Fluorescenttissue staining and microscopy was performed similar to methodspreviously described at Ikonomovic M D, Klunk W E, Abrahamson E E, etal., “Post-mortem correlates of in vivo PiB-PET amyloid imaging in atypical case of Alzheimer's disease”, Brain: A Journal Of Neurology2008; 131:1630-45. Meningioma and other brain tumor sections werestained with 100 nM CN-PiB, 100 nM of unlabeled PiB or with saline aloneas a negative control. The staining protocol was as follows:deparaffinization and rehydration, 0.25% KMnO₄ incubation, water wash,1% K₂S₂O₅/1% Oxalic Acid incubation, water wash, PBS wash,6-CN-PiB/PiB/saline incubation, PBS wash, NaCl, K₂HPO₄, and KH₂PO₄incubation, water wash, mount coverslip, and storage at 4° C. in thedark until imaged. Slides were imaged within five days of staining.Immunohistochemical staining of meningiomas for beta amyloid protein wasperformed using NCL-B-Amyloid mouse anti-human antibody per standardclinical protocol.

Fluorescent Microscopy

Tissue stain images were obtained on a Zeiss 510 confocal microscopewith excitation at 405 nm, a 420-480 bandpass filter, and the laser setat 15% power. Images were obtained with a C-Apochromat 40×/1.2 W lens.

Light Microscopy

Digital light microscopy images were obtained with NanoZoomer DigitalPathology (Hamamatsu). Color digital images were produced via a 3-CCDdigital camera. WebSlide Enterprise software (Olympus) was used toprocess the digital images.

Results

PiB PET/CT of Tumors and Lesions Identified on Imaging of the Head

Excluding tiny tumors, a total of 24 possible meningiomas wereidentified in the population of 834 patients. Of those 24 possiblemeningiomas, 16 tumors in 15 patients met our strict imaging criteriafor high-likelihood meningiomas. All 16 meningiomas were clearlydiagnostically positive on PiB PET/CT imaging. Among these 16 tumors,the average SUVmax (by body weight) was 2.2 (range 1.4-3.6). This levelof activity was well above the average background PiB activity in thesurrounding cerebrospinal fluid (SUVmax 0.2), and the average PiBactivity of nearby normal grey matter and bone (SUVmax 1.1 and 0.6respectively). Of note, 8 of these patients (53%) had high PiB retentionin cerebral grey matter per previously described criteria (See KantarciK, Lowe V, Przybelski S A, et al., “Magnetic resonance spectroscopy,{beta}-amyloid load, and cognition in a population-based sample ofcognitively normal older adults”, Neurology 2011; 77:951-8.), but thisdid not interfere with the identification of any meningiomas (forexample, see FIG. 3).

FIG. 3 shows a classic meningioma positive on PiB PET/CT. A 2.6 cm thickmeningioma arising from the meninges of the right tentorium andcompressing the right posterior temporal lobe (arrows). This tumor showsincreased density on non-contrast CT (Panel A), low signal onT1-weighted MRI images (Panel B; sagittal), high signal on T2-weightedimages (Panels C&D), uniform enhancement with an enhancing dural tail(Panels E&F coronal: arrow on F shows dural tail), and very slow growthover greater than 3 years (Panels C&D). This meningioma was highlyactive on PiB PET/CT (Panels G&H) with a SUVmax of 2.8. Of note, thispatient had increased PiB activity in the cerebral grey matterindicative of amyloid deposition. This meningioma showed only trace FDGactivity (Panels I&J).

The meningiomas had the following MRI and CT imaging characteristics:average thickness 1.4 cm (range 0.5-2.6); 11 had a dural tail sign; 10showed slow growth; 4 were calcified; 2 induced hyperostosis ofoverlying bone; and 1 was partially cystic. Meningiomas were foundadjacent to the peripheral cerebrum and cerebellum, tuberculum sellae,sella turcica, falx, internal auditory canal, cerebellar pontine angle,and within the lateral ventricle. Seven meningiomas had moderate to highFDG activity. The meningiomas were imaged with an average of 6.8 MRIscans and 1.0 diagnostic CT scans over an average of 6.3 years (range2.5-12.3). One person had 2 meningiomas. One person with a 2.0 cm thickmeningioma had focused irradiation 1 month prior to PiB PET/CT imaging,but still had PiB activity (SUVmax 3.6), after which the tumor appearedto stop growing on follow-up MRI 1 year later. Two patients were imagedwith PiB PET/CT more than once with stable or increasing SUVmax of theirmeningioma.

The population with meningiomas was similar to the general populationstudied. The general population were adult patients, average age 78.4years (standard deviation +/−7.1). 42% of the participants were women,and 32% had mild cognitive impairment. Those with meningiomas had anaverage age of 80.1 years (range 71-95). Eight (53%) of those withmeningiomas were female, and 5 (33%) had mild cognitive impairment.Fourteen patients (93%) had neurology and/or neurosurgery consultationfor their meningiomas in our records. Ten patients (67%) had a potentialdifferential diagnosis mentioned in the radiologist's interpretation, orin clinical notes. The differential diagnoses included metastasis,schwannoma, pituitary macroadenoma, sarcoidosis, choroid plexuspapilloma and ependymoma.

In contrast to the possible meningiomas, all non-meningioma intracranialtumors identified were negative on PiB PET/CT (SUVmax≦1.1). Eight of thenon-meningioma tumors were of types commonly confused with meningiomas;metastases (2), pituitary macroadenomas (3), schwannomas (2) and anependymoma. Other non-meningioma tumors included subependymal nodules,lipomas, choroid xanthogranulomas, pineal tumors, Rathke cleft cysts anda glioma. Numerous non-tumorous lesions were seen, including sub-acuteto chronic ischemic and hemorrhagic strokes, arachnoid cysts andmultiple sclerosis lesions that showed only trace PiB activity. Bonylesions such as hemangiomas, fibrous dysplasia, hyperostosis frontalisand an osteoma had PiB activity similar to, or only slightly higher thannormal bone (SUVmax <1.0). Extra-cranial tumors, such as sinus polyps,mucus retention cysts, mucocele, Warthin's tumors and an invertedpapilloma also had low PiB activity (SUVmax <1.2). Vascular lesions hadblood-pool-level PiB activity or less (SUVmax ≦1.2), includinganeurysms, telangiectasias, cavernomas and venous angiomas.

PiB PET/CT of Meningiomas Compared to Metastases

Meningiomas and intracranial metastases could be clearly differentiatedwith PiB PET/CT. FIG. 4 shows two examples. Both metastases werenegative on PiB PET/CT. Both metastases were later confirmedpathologically, from autopsy and surgery respectively.

FIG. 4 shows meningiomas compared to metastases on PiB PET fused to MRI.Two high-likelihood meningiomas on the left with contrast enhancedT1-weighted MRI, PiB PET and PiB PET fused to MRI (Panels A-C and G-I)compared to a melanoma metastasis (Panels D-F) and a small cell lungcancer metastasis (Panels J-L) in similar locations. SUVmax of thetumors were 2.8 and 3.6 for the meningiomas and 0.9 and 1.1 for themelanoma and small cell lung cancer metastases respectively. Bothmetastases and the meningioma in panels G-I had increased FDG PETactivity (not shown).

PiB PET/CT of Meningiomas Compared to Other Primary Tumors

Meningiomas and other common primary intracranial tumors could beclearly differentiated with PiB PET/CT. FIG. 5 shows comparison examplesof meningiomas and non-meningiomas in similar locations. In all theexamples shown the presumed tumor diagnosis was fairly confident withfollow-up MRI imaging alone. With the exception of the recurrentmeningioma, none of the tumors shown were biopsied. FIG. 3 also showstwo patients with previously surgically resected meningiomas; one withrecurrent meningioma and one with post-surgical scar. Of note, therecurrent meningioma shown in FIG. 5 panels M&N did not meet ourcriteria for high-probability meningioma, because there was no record ofa contrast enhanced MRI performed in this patient. Despite this, thetumor showed slow growth over 40+ years and was very likely a recurrentmeningioma.

FIG. 5 shows meningiomas compared to other intracranial tumors on PIBPET/CT and MRI. Sella/supracellar region: Enhanced T1-weighted MRI, PiBPET and PET/CT of a meningioma (SUVmax 1.7, Panel A) compared to PiBPET/CT, PET and FLAIR MRI of a pituitary macroadenoma (SUVmax 0.9, PanelB). The macroadenoma was positive on FDG PET/CT (not shown). Internalauditory canal: Enhanced T1-weighted MRI, PiB PET and PET/CT of ameningioma (SUVmax 1.9, Panel C) compared to PiB PET/CT, PET andenhanced T1-weighted MRI of a schwannoma (SUVmax 0.8, Panel D). Lateralventricle: FLAIR MRI, PET and PiB PET/CT of a meningioma (SUVmax 2.1,Panel E) compared to PiB PET/CT, PET and FLAIR MRI of an ependymoma(SUVmax 0.4, Panel F). Note the high level of nonspecific PiB activityin nearby normal white matter. Post-surgical meningioma recurrenceversus scar. FLAIR MRI, PiB PET and PET/CT of meningioma recurrence(SUVmax 1.5, Panel G) compared to PiB PET/CT, PET of postoperativechanges/scarring (SUVmax 0.6, Panel H) and enhanced T1-weighted MRI ofthe pre-surgical tumor (Panel H). Pathology from the initial resectionsof both tumors showed WHO grade I meningiomas.

Immunohistochemistry for Amyloid

Five surgically resected benign meningiomas all stained negative withamyloid specific antibodies (see example in FIG. 6). Alzheimer diseasedbrain tissue was used as positive control and stained positively (notshown).

Fluorescent PiB Staining

Fluorescent microscopy of meningiomas stained with PiB revealed a uniquestaining pattern. To further investigate the mechanism of PiB binding inmeningiomas, surgical and autopsy specimens of intracranial tumors werestained with PiB (not shown). PiB, like its parent compoundthioflavin-T, has some autofluorescence. These tumor tissues were alsostained with a highly fluorescent version of PiB (6-CN-PiB). FIG. 6shows an example meningioma stained positively with 6-CN-PiB. 6-CN-PiBstained with a similar pattern to PiB, and allowed for betterfluorescent images due to higher signal to background ratio.

FIG. 6 shows meningioma tissue stains compared to a schwannoma andamyloid plaques in the cerebral cortex. Enhanced T1-weighted MRI of ameningioma (Panel A) that was later surgically resected and stained withH&E (5×, Panel B), showing a classic appearance for a WHO grade Imeningothelial meningioma. Anti-amyloid antibody immunohistochemicalstaining of the same meningioma shows complete absence of stain (PanelC), indicating lack of amyloid. 6-CN-PiB staining of the same meningiomashows intense fluorescence, most intense in the nuclei (Panel D). Thisis compared to a schwannoma, which shows only trace fluorescence (PanelE) and amyloid laden cerebral cortex from a patient who had Alzheimer'sdisease, which shows very intense fluorescence of amyloid plaques(positive control). Note the absence of nuclear staining pattern inpanels E and F.

The staining in all meningiomas (n=7) was qualitatively brighter thanthat seen in other intracranial tumors (n=6). The pattern of staining inmeningiomas was brightest in the nuclei. This pattern was reproduciblewith WHO grade 1, 2 and 3 meningiomas. More specifically, the nuclearstaining pattern appeared brightest near the nuclear envelope in theperiphery of the nuclei, perhaps in the areas of heterochromatin. Thispattern of staining differed dramatically from that seen in Alzheimer'sdiseased brain gray matter (FIG. 4), and normal brain white matter (notshown). Normal brain gray matter showed almost no fluorescence (notshown). Moderate 6-CN-PiB binding was seen in some other tumors, but thestaining pattern was different. For example, scattered fluorescence in alung cancer metastasis may have been due to nonspecific binding in areasof tissue necrosis (not shown), and therefore may not directly correlateto findings on PET scans.

Discussion

We have shown here in a study in 834 patients that PiB PET/CT canidentify meningiomas and differentiate from other intracranial tumors,including metastases. Our data shows PiB PET/CT to be 100% sensitive andspecific for meningiomas 5 mm and thicker compared to all other tumorsidentified in the population studied. PiB was initially designed to bindto amyloid plaques seen in the brains of patients with Alzheimerdisease. However, we provide evidence here that meningiomas do notcontain amyloid and that PiB may be binding to something novel andperhaps unique to meningiomas. Tissue stains suggest the most likelybinding location is within the nuclei of the cells of the meningiomas,and may reside within areas of heterochromatin.

PiB PET/CT may help resolve common diagnostic dilemmas in brain tumordiagnosis. While many meningiomas are diagnosed with confidence onfollow-up MRI scans, differentiating meningiomas from life-threateningbrain tumors on a single scan presents a challenge. The generalcategories or etiologies of meningioma-like masses include metastaticdisease, lymphoma, plasmacytoma, primary dural tumors, infections,inflammatory tumors, and other systemic diseases. Metastases are themost common tumors to be confused with meningiomas and often requiredrastically different therapy. In addition to meningeal spread,metastases are seen commonly in the peripheral brain parenchyma, wherethey can be indistinguishable from meningeal masses on MRI and CT.

The clinical scenario of the patient in our study with melanomametastasis emphasizes the potential usefulness of this technology. Inthis case the tumor was incidentally detected on an MRI that wasperformed for evaluation of a stroke. This patient had her primarymelanoma resected from her neck six years prior. She had no history ofmetastasis. Whole body FDG PET/CT did not reveal any other tumors. Theradiologist's interpretation of the initial brain MRI gave adifferential that included meningioma and metastasis; thereforefollow-up MRI scans were performed. On follow-up imaging over fivemonths rapid tumor growth was seen, which lead to brain biopsy for finaldiagnosis. Pathology showed the metastasis was actually in the peripheryof the cerebral cortex, not truly in the meninges. At initial imagingthe tumor was large enough to be detectable by PET/CT technology, as itwas positive on FDG PET/CT. But since meningiomas can be FDG avid, thisdid not narrow the differential diagnosis. However, the tumor wasnegative on the research PiB PET/CT. Therefore, based on the data wepresent in this study, the tumor was unlikely to be a meningioma, andaggressive therapy could have been initiated much earlier.

CONCLUSIONS

We show here that PiB PET/CT has the potential to become a usefuladjunct to MRI and CT imaging for the diagnosis of meningiomas. Tumorimaging with PiB PET/CT represents a new type of tumor imaging notpreviously described. The exact mechanism of PiB binding in meningiomasis not clear, but PiB is likely binding to something other than amyloidwithin meningiomas.

Prophetic Example A

One would administer the compound of Formula (X) to a patient withpresumed meningioma. The compound of formula (X) is also known asFlorbetapir, or ¹⁸F-AV-45. One would acquire a combined PET/CT image todetect the presence or absence of any meningiomas in the patient. Onewould envision that PET/CT data would confirm meningioma uptake ofFormula (X). One would envision that other stilbene derivatives wouldconfirm meningioma uptake.

Prophetic Example B

One would administer the compound of Formula (XI) to a patient withpresumed meningioma. The compound of formula (XI) is also known asFlorbetapen, or AV-1, or BAY94-9172. One would acquire a combined PET/CTimage to detect the presence or absence of any meningiomas in thepatient. One would envision that PET/CT data would confirm meningiomauptake of Formula (XI). One would envision that other biphenylalkynederivatives would confirm meningioma uptake.

Thus, the invention provides a method for the imaging of meningiomasusing a phenylbenzothiazole derivative or a stilbene derivative or abiphenylalkyne derivative, and using a medical imaging technique such aspositron emission tomography imaging. More particularly, the inventionprovides a method for the imaging of meningiomas using Pittsburghcompound B or Florbetapir or Florbetapen, and a medical imagingtechnique such as positron emission tomography with computed tomographyimaging.

The clinical scenarios where this technology could be useful include:(1) when a tumor that could be a meningioma is identified in a patientwith a history of cancer, (2) when a probable meningioma is in alocation where other common primary brain tumors arise, (3) when ameningioma has been resected and there is a mass on follow-up imagingthat might be a meningioma recurrence or a scar, and lastly (4) forradiation therapy planning. PiB PET/CT may help to expedite and improvepatient care by eliminating the need for delayed follow-up imaging orbiopsy to confirm tumor diagnosis.

Although the present invention has been described in detail withreference to certain embodiments, one skilled in the art will appreciatethat the present invention can be practiced by other than the describedembodiments, which have been presented for purposes of illustration andnot of limitation. Therefore, the scope of the appended claims shouldnot be limited to the description of the embodiments contained herein.

What is claimed is:
 1. A method for detecting or ruling out a meningioma in a patient, the method comprising: (a) administering to a patient a detectable amount of a compound of formula (I):

wherein the compound is targeted to any meningiomas in the patient; and (b) acquiring an image to detect the presence or absence of any meningiomas in the patient, wherein R₁ is OH, R₂ is H, and R₃ is NH¹¹CH₃, and wherein the meningiomas do not contain amyloid.
 2. The method of claim 1 wherein: step (b) comprises acquiring the image using an imaging method selected from positron emission tomography imaging, positron emission tomography with computed tomography imaging, positron emission tomography with magnetic resonance imaging, or any combination thereof.
 3. The method of claim 1 wherein: step (b) comprises acquiring the image using positron emission tomography imaging.
 4. The method of claim 1 wherein: step (b) comprises acquiring the image using positron emission tomography with computed tomography imaging.
 5. The method of claim 1 wherein: step (b) comprises acquiring the image using positron emission tomography with magnetic resonance imaging.
 6. The method of claim 1 wherein: the presence of any meningiomas in the patient is indicated by an image in which meningiomas showed activity of the compound greater than normal adjacent tissues imaged.
 7. The method of claim 1 wherein: the presence of any meningiomas in the patient is indicated by a brain image in which meningiomas showed activity of the compound greater than any other intracranial tumors imaged.
 8. The method of claim 1 wherein: the presence of any meningiomas in the patient is indicated by a brain image in which meningiomas showed activity of the compound greater than any metastases, pituitary macroadenomas, schwannomas, or ependymomas imaged.
 9. The method of claim 1 wherein: the presence of any meningiomas in the patient is indicated by an image in which meningiomas showed activity of the compound greater than any metastases imaged.
 10. A method for detecting or ruling out a meningioma in a patient, the method comprising: (a) administering to a patient a detectable amount of a compound of formula (V):

wherein the compound is targeted to any meningiomas in the patient; and (b) acquiring an image using positron emission tomography imaging to detect the presence or absence of any meningiomas in the patient, wherein the meningiomas do not contain amyloid.
 11. The method of claim 10 wherein: the presence of any meningiomas in the patient is indicated by an image in which meningiomas showed activity of the compound greater than normal adjacent tissues imaged.
 12. The method of claim 10 wherein: the presence of any meningiomas in the patient is indicated by a brain image in which meningiomas showed activity of the compound greater than any other intracranial tumors imaged.
 13. The method of claim 10 wherein: the presence of any meningiomas in the patient is indicated by a brain image in which meningiomas showed activity of the compound greater than any metastases, pituitary macroadenomas, schwannomas, or ependymomas imaged.
 14. The method of claim 10 wherein: the presence of any meningiomas in the patient is indicated by an image in which meningiomas showed activity of the compound greater than any metastases imaged. 